Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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MUSCARINIC AGONISTS
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical and organic
chemistry
and provides crystalline compounds that are active at the muscarinic
receptors.
BACKGROUND OF THE INVENTION
Biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide is
described
in PCT Publication Number WO 03/027061, published April 3, 2003. The forms of
the
compound described in the above patent application are an anhydrous form and
the
acetonitrile solvate.
The present invention provides crystalline biphenyl-4-carboxylic acid (R)-(6-
(1-
((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate, compositions thereof, methods of using the same, and processes
for making
the same. The crystalline hemihydrate of the present invention is useful as a
selective
agonist of the muscarinic M-1 receptor and, as such, is useful for treating a
variety of
disorders of the central nervous system and other body systems. These
disorders include
cognitive disorders, ADHD, obesity, Alzheimer's disease, psychoses including
schizophrenia, and for alleviation of intraocular pressure such as that found
in glaucoma.
Because biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide is
useful for
treating disorders associated with muscarinic receptors, there is a need to
produce it as a
pure, stable, and crystalline form in order to fulfill exacting pharmaceutical
requirements
and specifications. The novel crystalline hemihydrate of this invention has
suitable
properties to be conveniently formulated on a commercial scale in, for
example, tablets
for oral administration, and has suitable processing and storage properties.
In particular,
the present crystalline hemihydrate is a form that is easy to make in a
reproducible and
consistent manner. Furthermore, the novel crystalline hemihydrate of this
invention
exhibits greater thermodynamic stability.
It has been surprisingly discovered that biphenyl-4-carboxylic acid (R)-(6-(1-
((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide can be
prepared in a hemihydrate form and having advantageous properties and the
manufacturing process for the new form fulfills the desirable features
described above.
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SUMMARY OF THE INVENTION
The present invention provides biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate.
In another embodiment, the present invention provides a pharmaceutical
composition comprising biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
and a pharmaceutically acceptable diluent.
Because the compounds of the present invention are agonists of the M-1
muscarinic receptor, the compounds of the present invention are useful for the
treatment
of a variety of disorders associated with muscarinic receptors, including:
cognitive
disorders (including age-related cognitive disorder, mild cognitive
impairment, cognitive
impairment associated with schizophrenia, and chemotherapy-induced cognitive
impairment), ADHD, mood disorders (including depression, mania, bipolar
disorders),
psychosis (in particular schizophrenia), dementia (including Alzheimer's
disease, AIDS-
induced dementia, vascular dementia, and dementia lacking distinctive
histology),
Parkinson's disease, and Huntington's Chorea. Also, the present compounds are
useful
for treating chronic colitis, including Crohn's disease. Additionally, the
present
compounds are useful for the treatment of pain (including acute pain and
chronic pain),
xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body
disease),
aphasia (including primary aphasia and primary aphasia syndromes), and
hypotensive
syndromes.
In one of its method aspects, this invention is directed to a method for
treating
disorders associated with the muscarinic receptors comprising administering to
a patient
in need thereof an effective amount of biphenyl-4-carboxylic acid (R)-(6-(1-
((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate.
The present invention provides biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
for use in therapy. The present invention provides for the use of biphenyl-4-
carboxylic
acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-
1-
yl)amide hemihydrate for the manufacture of a medicament for the treatment of
disorders
associated with muscarinic receptors.
In another embodiment this invention provides a process for making biphenyl-4-
carboxylic acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-
hydroxyindan-1-yl)amide hemihydrate.
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DETAILED DESCRIPTION OF THE INVENTION
Herein, the Cahn-Prelog-Ingold designations of (R)- and (S)- and the
designations
of L- and D- for stereochemistry relative to the isomers of glyceraldehyde are
used to
refer to specific isomers.
The present invention provides biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate, and in particular, a crystalline biphenyl-4-carboxylic acid (R)-
(6-(1-((4
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate.
A number of methods are available to characterize crystalline forms of organic
compounds. For example, methods include differential scanning calorimetry,
thermogravimetric analysis, solid state NMR spectrometry, infra-red
spectroscopy, and
X-ray powder diffraction. Among these, X-ray powder diffraction and solid
state NMR
spectroscopy are very useful for identifying and distinguishing between
crystalline forms.
X-ray powder diffraction analysis was performed as follows. Either with or
without lightly grinding with an agate mortar and pestle, the dry sample is
loaded into a
recessed top-loading sample holder and the surface is smoothed with a glass
slide. The X-
ray powder diffraction patterns were measured using a Siemens D5000 X-ray
powder
diffractometer equipped with a CuKa source (~, = 1.540560 operated at 50 kV
and 40
mA using divergence slit size of 1 mm, receiving slit of 1 mm, and detector
slit of 0.1
mm. Each sample was scanned between 4° and 35° (28) with a step
size of 0.02° and a
maximum scan rate of 3 sec/step. Data is collected using a Kevex solid-state
silicon
lithium detector. Optimally, a silicon standard is run routinely to check the
instrument
alignment.
It is well known in the crystallography art that, for any given crystal form,
the
relative intensities and peak widths of the diffraction peaks may vary due to
a number of
factors, including the effects of preferred orientation and/or particle size.
Where the
effects of preferred orientation and/or particle size are present, peak
intensities may be
altered, but the characteristic peak positions of the polymorph are unchanged.
See, e.g.,
The United States Pharmacopoeia #24, National Formulary #19, pages 1843-1844,
2000.
Furthermore, it is also well known in the crystallography art that, for any
given crystal
form, the angular peak positions may vary slightly. For example, peak
positions can shift
due to sample displacement or a variation in the temperature or relative
humidity at which
a sample is analyzed. In the present case, a peak position variability of ~
0.1 ° in 28 will
take into account these potential variations without hindering the unequivocal
identification of the crystalline form of the present invention.
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The angular peak positions in 28 and corresponding relative intensity data for
all
peaks with intensities equal to or greater than 5 to 10% of the largest peak
for biphenyl-4-
carboxylic acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-
hydroxyindan-1-yl)amide hemihydrate are listed in Table 1.
Peak position was obtained in 28 values and peak intensities for the most
prominent features (relative intensities greater than 5 to 10%) were measured
using a
double-derivative peak picking method.
Accordingly, the present invention includes the particular crystal biphenyl-4-
carboxylic acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-
hydroxyindan-1-yl)amide hemihydrate characterized by the angular peak
positions in 28
and corresponding relative intensity data in Table 1, which lists the 28
values and relative
intensities greater than 5 to 10% using the methodology described above with
CuKa
radiation:
Un ro und 5 min 'ndin
28 I/I, oo 28 () I/I, oo
% (%
5.2 17.1 5.2 16.2
6.2 8.0 6.2 1 0.6
12.6 100 12.6 100
14.0 23.7 13.9 20.3
14.4 15.8 14.5 12.6
14.9 12.2 14.9 10.8
15.6 39.1 15.6 37.0
17.0 29.0 16.9 26.2
18.8 49.9 18.8 58.6
19.6 29.8
20.0 52.2 20.0 91.6
20.9 7.7 20.9 13.5
21.7 5.7 21.7 13.7
22.6 30.4 22.6 52.1
23.3 15.9 23.2 21.1
25.9 14.1 25.9 20.0
26.5 9.4 26.4 12.3
27.5 5.4 27.4 6.5
Table 1
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The intensities of the sample ground for 5 minutes are representative of the
diffraction pattern where attempts were made to minimize the effects of
preferred
orientation and/or particle size. It should also be noted that the computer-
generated
numbers are listed in this table.
S Thus, a properly prepared crystalline sample of biphenyl-4-carboxylic acid
(R)-(6-
( 1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate may be characterized by X-ray diffraction pattern in 28 values
using CuKa
radiation having peaks as described in Table 1, and in particular having a
peak at 5.2, 6.2,
12.6, 14.0, 15.6, 17.0, 18.8, 19.6, 20.0, or 22.6; more particularly having a
peak at 5.2,
6.2, 12.6, 15.6, 18.8, or 20.0; peaks at any two of 5.2, 6.2, 12.6, 15.6,
18.8, and 20.0; or
having peaks at 5.2, 6.2, 12.6, 14.0, 15.6, 17.0, 18.8, 19.6, 20.0, and 22.6.
Crystalline biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
may also be characterized by solid state NMR spectroscopy. Solid state ' 3C
chemical
shifts reflect not only the molecular structure of but also the electronic
environment of the
molecule in the crystal.
Solid state NMR ('~C) spectroscopy can be carried out using'3C cross
polarization/magic angle spinning (CP/MAS). NMR (solid-state NMR or SSNMR)
spectrum was obtained using a Varian Unity Inova 400 MHz spectrometer
operating at a
carbon frequency of 100.573 MHz, equipped with a complete solids accessory and
a
Chemagnetics 4.0 mm T3 probe. Acquisition parameters were as follows:
90° proton r.f.
pulse width 4.0 ~s, contact time 2.0 ms, pulse repetition time 10 s, MAS
frequency 10.0
kHz, spectral width 50 kHz, and acquisition time 50 ms. Chemical shifts were
referenced
externally to the methyl group of hexamethylbenzene (8 = 17.3 ppm), that is,
by sample
replacement with hexamethylbenzene.
The spectrum for biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
comprises isotropic peaks at the following chemical shifts: 15.4, 17.8, 35.3,
38.1, 39.3,
40.2, 54.1, 63.4, 81.6, 84.7, 116.9, 118.1, 120.2, 121.5, 124.7, 126.7, 129.0,
131.9, 133.0,
134.0, 135.0, 136.7, 137.5, 140.4, 141.7, 143.9, 151.6, 154.5, 156.8, 160.4,
162.2, 162.9,
164.6, and 169.8 ppm.
In another embodiment this invention provides a process for making biphenyl-4-
carboxylic acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-
hydroxyindan-1-yl)amide hemihydrate comprising crystallizing biphenyl-4-
carboxylic
acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-
1-
yl)amide from a suitable solvent under conditions which yield biphenyl-4-
carboxylic acid
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(R)-(6-( 1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-
yl)amide hemihydrate.
The precise conditions under which biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
is formed may be empirically determined and it is only possible to give a
number of
methods which have been found to be suitable in practice.
Thus, for example, biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
hemihydrate
may be prepared by crystallization under controlled conditions.
Crystallization from a
solution and slurrying techniques are contemplated to be within the scope of
the present
process. In particular, the hemihydrate of the present invention can be
prepared by
crystallization from an aqueous-alcohol solvent mixture, including methanol-
water,
ethanol-water, isopropanol-water, methanol-isopropanol/water, and methanol-
acetonitrile/water. A suitable solvent is one that is capable of containing
sufficient water,
at the concentrations used, to form the present hemihydrate. In practice, it
has been found
that methanol-water is preferred.
The use of an anti-solvent may be advantageous. As used in the context of the
present process, the term "anti-solvent" refers to a solvent in which biphenyl-
4-carboxylic
acid (R)-(6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-
1-
yl)amide hemihydrate is significantly less soluble relative to the selected
solvent.
Preferably, when an anti-solvent is used it is miscible with the selected
solvent.
A crystallization is generally carried out by dissolving biphenyl-4-carboxylic
acid
(R)-(6-( 1-((4-fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-
yl)amide hemihydrate in an organic solvent and adding an anti-solvent, for
example,
water, to give a solid. In particular, slow anti-solvent addition of water to
an alcoholic
solution of the compound between ambient and 60°C is the preferred
method of
crystallization. Elevated temperatures for excessive periods of time can cause
hydrolysis
in aqueous media; thus, lower temperatures are preferred. Seeding may be
advantageous.
Preferably the crystallization solution is cooled slowly. The crystallization
is most
conveniently cooled to temperatures of ambient temperature to about
0°C.
The present invention is further illustrated by the following examples and
preparations. These examples and preparations are illustrative only and are
not intended
to limit the invention in any way.
The terms used in the examples and preparations have their normal meanings
unless otherwise designated. For example, "°C" refers to degrees
Celsius; "M" refers to
molar or molarity; "mmol" refers to millimole or millimoles; "g" refers to
gram or grams;
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"mL" refers milliliter or milliliters; "mp" refers to melting point; "brine"
refers to a
saturated aqueous sodium chloride solution; etc. In the'H NMR, all chemical
shifts are
given in 8, unless otherwise indicated.
EXAMPLE 1-1
Biphenyl-4-carboxylic acid (R)-(6-(I-((4-
fluorobenz~)methylamino)ethylideneamino)
2(Rl-hydroxyindan-1-yl)amide
0
F
CHs HN ~ \
\ N~N \
CH3 ~ / " pH ~ /
Slowly add a solution of 375 g (5.13 mol, 1.12 equiv) of N-methylacetamide in
THF (1.76 L) to 224 g (5.55 mol, 1.2 equiv) of sodium hydride (60% dispersion
in
mineral oil) as a slurry in THF (8.75 L). After 30 minutes when 25% of the
solution has
been added, add 875 g (4.63 mole, 1 equiv) of 4-fluorobenzylbromide and the
remaining
N-methylacetamide and 4-fluorobenzylbromide solutions concurrently over the
next 3 h.
Use a water bath to maintain the temperature below 40°C. Stir the
resulting mixture
overnight and pour into a mixture of 20% NH4C1 (2.5 L), water (6.5 L), and
ethyl acetate
(9 L). Separate the layers and back-extract the aqueous layer with ethyl
acetate (4.5 L,
then 2 L). Combine the organic layers and wash with water (4 L) and then brine
(7 L).
Dry the organic layer (Na2S04) and remove the solvent to afford a residue.
Dissolve the
residue in acetonitrile (7 L) and heptane (1.75 L). Separate the layers and
wash the
acetonitrile layer again with heptane (1.75 L). Combine the heptane layers and
back-
extract with acetonitrile (0.5 L). Combine the acetonitrile layers and
evaporate to afford
0.814 kg of N-methyl-N-(4-fluorobenzyl)acetamide.
Dissolve N-methyl-N-(4-fluorobenzyl)acetamide (0.500 kg, 2.76 mol) in THF
(11.5 L). Add phosphorus pentasulfide (0.737 kg, 1.65 mol, 0.6 equiv) and heat
the
mixture to reflux over 1-2 hours. After 5 h at reflux, allow the mixture to
cool to room
temperature, filter off the solids, and wash with 12.5 L of THF. Combine the
filtrate with
an identical filtrate from a separate reaction and concentrate to 0.978 kg of
a residue.
Dissolve the residue and chromatograph on 2.7 kg of silica gel using CH2C12 to
afford
1.01 kg of solid. Slurry the solid with methylene chloride (1 L) for 15-30
min, add
heptane (5 L), cool the mixture to 0-5°C, and stir for 2 h. Collect the
solid by filtration
and dry to afford 0.814 kg of N-methyl-N-(4-fluorobenzyl)thioacetamide.
Add 11.5 L of acetonitrile and 2.52 kg (17.7 mol, 1.5 equiv) of methyl iodide
to
2.30 kg (11.6 mol) of N-methyl-N-(4-fluorobenzyl)acetamide. Heat the mixture
to 35 °C
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_g_
for 21 h. Reduce the volume by half on a rotary evaporator and add 14 L of
MTBE.
Reduce the volume again by half and add another 14 L of MTBE. Cool the
resulting
slurry to 0 °C, collect the solid by filtration, and dry to afford 3.92
kg of 1-methylthio-1-
methyl-N-(4-fluorobenzyl)-N-methylimmonium iodide as a white solid.
Add 85 L of concentrated NH40H and 28 L of water to 6.20 kg (35.0 mol) of 1,2-
epoxy-6-nitroindane. Heat the mixture at 36 °C for 21 h and allow to
cool to room
temperature. Filter the reaction mixture over a bed of wet Celite (10 kg) and
rinse the
cake with water. To a wet filter cake of (1R,2R)-1-amino-6-nitroindan-2-of
prepared
from 6.20Add to the wet cake 155 L of methanol, 1.3 L of water, and 5.80 kg
(38.1 mol,
1.09 equiv) of (S)-(+)-mandelic acid. Heat the mixture for 2 h at 55 °C
and filter through
a carbon impregnated filter cartridge. Reduce the filtrate volume by vacuum
distillation
to about 35 L and add 130 L of EtOAc. Reduce the volume by vacuum distillation
to
about 65 L. Cool the mixture to -8 °C and stir for 8 h. Filter the
slurry and dry the solid
to afford 7.6 kg of a solid. Slurry this solid in 30 L of methanol and 0.3 L
of water, and
heat the mixture at reflux for 0.5 h. Cool the mixture to 45 °C over
0.5 h and stir for 12 h,
followed by cooling to 22 °C and stirring for 10 h. Collect the solid
by filtration and dry
to afford 2.7 kg of ( 1 R,2R)-1-amino-6-nitroindan-2-of (S)-mandelate.
Add (1R,2R)-1-amino-6-nitroindan-2-of mandelate (0.64 kg, 1.85 mol) to a
mixture of toluene (9.6 L) and aqueous 1 N NaOH (4.8 L, 4.8 mol, 2.6 equiv).
After 1 h,
add 4-biphenylcarbonyl chloride (0.44 kg, 2.0 mol, 1.1 equiv) in portions over
20-30 min.
After 22 hours, filter the solids under vacuum and rinse sequentially with 0.5
L of
toluene, 2 L of water, and 2 L of toluene. Dry the cake to afford 0.74 kg of
biphenyl-4-
carboxylic acid (R)-(6-nitro-2-hydroxyindan-1-yl)amide. Add 38.2 L of ethyl
acetate to
1.914 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-
y1)amide
prepared in a similar manner. Stir the slurry for 18 h, collect the solid by
filtration, dry to
afford 1.76 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-
yl)amide
as a white solid.
Combine a slurry of 0.176 kg of 10% Pd-C (50% water wet) and 1.7 kg of
biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide in 17.5 L
of DMF
with hydrogen (50 psi, 345 kPa). After 19 h, filter the reaction mixture, add
a portion of
the DMF solution (5 L) to water (10 L), and stir the slurry for 2 h - repeat
twice to work
up the entire reaction volume. Filter the slurries together, and wash the
resulting filter
cake with water (3 x 7 L). Dry the filter cake to afford 1.42 kg of biphenyl-4-
carboxylic
acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide.
Slurry biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide
(0.969 kg, 2.81 mol) in THF (9.7 L) and add 1-methylthio-1-methyl-N-(4-
fluorobenzyl)-
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N-methylimmonium iodide (0.954 kg, 2.81 mol) and 4-dimethylaminopyridine (34.5
g,
0.281). Stir the mixture for 24 h, and remove the solvent in vacuo. Dissolve
the resulting
foam in CHZC12 (12.5 L) and wash the organic phase with 1.0 N HCl (1 x 4 L and
1 x 3
L), 1.0 M NaOH (1 x 2.4 L) and saturated NaCI (1 x 4 L). Separate the organic
phase,
dry (Na2S04), filter, and remove the solvent to yield a solid. Dissolve the
solid in
acetonitrile (9 L) while heating to 35-40 °C. After approximately 30
minutes, add seed
crystals, which results in a thick, white slurry. Cool the mixture to -15
°C and stir at this
temperature for 1-2 h. Filter the slurry and dry to provide 1.10 kg of the
title compound
as a partial acetonitrile solvate.
'H NMR (CDC13): 8 7.90 (d, 2, J = 8.6), 7.69 (d, 2, J = 8.6), 7.63 (d, 2, 3 =
8.2),
7.48 (t, 2, J = 8.2, 7.6), 7.41 (d, 1, J = 7.3), 7.24 (dd, 2, J = 8.5, 5.2),
7.14 (d, l, J = 7.9),
7.04 (t, 2, J = 8.7), 6.72-6.63 (m, 3), 5.31 (t, 1, J = 5.6), 4.84 (br s, 1),
4.64 (dd, 2, J =
21.4, 15.6), 4.54 (dd, 1, J = 14.0, 7.9), 3.32 (dd, l, J = 15.6, 7.9), 3.01
(s, 3), 2.95 (dd, 1, J
= 15.7, 8.0), 1.97 (s, 3). MS (m/z): 508.2 (M+1).
EXAMPLE P-1
Bi~hen~-4-carbox~ic acid (R)~6-(1-(~4-
fluorobenzyl)methylamino)ethylideneamino)
~Rl-hydroxyindan-1-yl)amide hemihydrate
Add 21.8 L of methanol to 2.86 kg of biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
acetonitrile
solvate. Pass the solution through a carbon impregnated filter and rinse the
filter with 24
L of methanol. Add 5.7 kg of water to the solution over 35 min followed by 15
g of
biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-
2(R)-hydroxyindan-1-yl)amide hemihydrate seed crystals. After 20 min, add 1.15
kg of
water followed by 15 g of seed crystals. After 1 h, add another 1.15 kg of
water over 30
min followed by 1 S g of seed crystals. After 10 min, add 3.4 kg of water over
1 h and stir
the slurry at room temperature for 1 h and at 0 °C for 45 min. Collect
the solid by
filtration, rinse with a cold solution of 11.4 L of methanol and 2.9 L of
water, and dry to
afford 2.19 kg of the title compound as a white solid.
Additionally, one of ordinary skill in the art will recognize that two
alternate
names for this crystalline compound are [1,1'-biphenyl]-4-carboxamide N-
[(1R,2R)-6-
[[ 1-[[(4fluorophenyl)methyl]methylamino]ethylidene]amino]-2,3-dihydro-2-
hydroxy-1 H-
inden-1-yl]-, hydrate (2:1) and 6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2-
hydroxy-1-biphenylamidoindane hemihydrate.
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EXAMPLE P-2
Biphen~-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)
2(R)-hydroxyindan-1-yl)amide hemihydrate
Dissolve biphenyl-4-carboxylic acid (R)-(6-(1-((4-
fluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide
acetonitrile
solvate (2.0 g) in methanol (24 mL) at 20-23 °C. Add water (5 mL) to
the solution,
followed by hemihydrate seed crystals (20 mg). Stir the mixture for 2 h at 20-
23 °C, then
cool to 0-5 °C. Filter the mixture, wash with a solution of methanol (8
mL) and water (2
mL), and dry at 50-60 °C under vacuum for 16 h to give 1.66 g of the
title compound.
EXAMPLE P-3
Biphen~-4-carbox~ic acid (R)-(6~1-((4-
fluorobenzyl)methylamino)ethylideneamino)
2(R)-hydroxyindan-1-yl)amide hemihydrate
Combine a solution of 6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)-2-
hydroxy-1-biphenylaminoindane acetonitrile solvate (101 g) and methanol (1.2
L) with
Darco G-60 (5 g). After stirring for 15-30 min at 15-25 °C, filter the
mixture and rinse
the filtered solids with methanol (0.4 L). Add water (0.4 L) to the combined
filtrate,
rinse, and add hemihydrate seed crystals (1.5 g). Stir the mixture 2-3 h at 15-
25 °C, then
cool to 0-5 °C and stir another 90 min. Filter the mixture, wash with a
0-5 °C solution of
methanol (0.8 L) and water (0.2 L), and dry at 47-53 °C under vacuum
for 20 h to give
88.7 g of the title compound.
The compounds of the present invention can be administered alone or in the
form
of a pharmaceutical composition, that is, combined with pharmaceutically
acceptable
carriers or excipients, the proportion and nature of which are determined by
the solubility
and chemical properties of the compound selected, the chosen route of
administration,
and standard pharmaceutical practice. The compounds of the present invention,
while
effective themselves, may be formulated and administered in the form of their
pharmaceutically acceptable salts, for purposes of stability, convenience,
solubility, and
the like. In practice, the compounds of the present invention are usually
administered in
the form of pharmaceutical compositions, that is, in admixture with
pharmaceutically
acceptable carriers or diluents.
Thus, the present invention provides pharmaceutical compositions comprising a
compound of the present invention and a pharmaceutically acceptable diluent.
The
present invention also provides suitable packaging, including a label,
containing the
pharmaceutical compositions comprising a compound of the present invention .
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The compounds of the present invention can be administered by a variety of
routes. In effecting treatment of a patient afflicted with disorders described
herein, a
compound of the present invention can be administered in any form or mode
which
makes the compound bioavailable in an effective amount, including oral and
parenteral
routes. For example, compounds of the present invention can be administered
orally, by
inhalation, subcutaneously, intramuscularly, intravenously, transdermally,
intranasally,
rectally, occularly, topically, sublingually, buccally, and the like. Oral
administration is
generally preferred for treatment of the disorders described herein.
One skilled in the art of preparing formulations can readily select the proper
form
and mode of administration depending upon the particular characteristics of
the
compound selected, the disorder or condition to be treated, the stage of the
disorder or
condition, and other relevant circumstances. (Remin~ton's Pharmaceutical
Sciences, 18th
Edition, Mack Publishing Co. (1990)).
The pharmaceutical compositions are prepared in a manner well known in the
pharmaceutical art. The Garner or excipient may be a solid, semi-solid, or
liquid material
which can serve as a vehicle or medium for the active ingredient. Suitable
carriers or
excipients are well known in the art. The pharmaceutical composition may be
adapted for
oral, inhalation, parenteral, or topical use and may be administered to the
patient in the
form of tablets, capsules, aerosols, inhalants, suppositories, solutions,
suspensions, or the
like.
The compounds of the present invention may be administered orally, for
example,
with an inert diluent or capsules or compressed into tablets. For the purpose
of oral
therapeutic administration, the compounds may be incorporated with excipients
and used
in the form of tablets, troches, capsules, elixirs, suspensions, syrups,
wafers, chewing
gums and the like. These preparations should contain at least 4% of the
compound of the
present invention, the active ingredient, but may be varied depending upon the
particular
form and may conveniently be between 4% to about 70% of the weight of the
unit. The
amount of the compound present in compositions is such that a suitable dosage
will be
obtained. Preferred compositions and preparations according to the present
invention may
be determined by a person skilled in the art.
The tablets, pills, capsules, troches, and the like may also contain one or
more of
the following adjuvants: binders such as microcrystalline cellulose, gum
tragacanth or
gelatin; excipients such as starch or lactose, disintegrating agents such as
alginic acid,
Primogel, corn starch and the like; lubricants such as magnesium stearate or
Sterotex;
glidants such as colloidal silicon dioxide; and sweetening agents such as
sucrose or
saccharin may be added or a flavoring agent such as peppermint, methyl
salicylate or
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orange flavoring. When the dosage unit form is a capsule, it may contain, in
addition to
materials of the above type, a liquid carrier such as polyethylene glycol or a
fatty oil.
Other dosage unit forms may contain other various materials which modify the
physical
form of the dosage unit, for example, as coatings. Thus, tablets or pills may
be coated
with sugar, shellac, or other coating agents. A syrup may contain, in addition
to the
present compounds, sucrose as a sweetening agent and certain preservatives,
dyes and
colorings and flavors. Materials used in preparing these various compositions
should be
pharmaceutically pure and non-toxic in the amounts used.
For the purpose of oral and parenteral therapeutic administration, the
compounds
of the present invention may be incorporated into a solution or suspension.
These
preparations typically contain at least 0.1 % of a compound of the invention,
but may be
varied to be between 0.1 and about 90% of the weight thereof. The amount of
the
compound of the present invention present in such compositions is such that a
suitable
dosage will be obtained. The solutions or suspensions may also include one or
more of
the following adjuvants: sterile diluents such as water for injection, saline
solution, fixed
oils, polyethylene glycols, glycerine, propylene glycol or other synthetic
solvents;
antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants
such as
ascorbic acid or sodium bisulfate; chelating agents such as ethylene
diaminetetraacetic
acid; buffers such as acetates, citrates or phosphates and agents for the
adjustment of
tonicity such as sodium chloride or dextrose. The parenteral preparation can
be enclosed
in ampoules, disposable syringes or multiple dose vials made of glass or
plastic. Preferred
compositions and preparations are able to be determined by one skilled in the
art.
The compounds of the present invention may also be administered topically, and
when done so the carrier may suitably comprise a solution, ointment, or gel
base. The
base, for example, may comprise one or more of the following: petrolatum,
lanolin,
polyethylene glycols, bees wax, mineral oil, diluents such as water and
alcohol, and
emulsifiers, and stabilizers. Topical formulations may contain a concentration
of the
compound of the present invention or its pharmaceutical salt from about 0.1 to
about 10%
w/v (weight per unit volume).
The compounds of the present invention are agonists of the M-1 muscarinic
receptors. Moreover the compounds of the present invention are selective
agonists of that
particular muscarinic receptor. The compounds of the present invention possess
particularly useful properties related to their bioavailability,
pharmacokinetics, safety, and
efficacy. Muscarinic agonists, including their subtype binding profile, can be
identified
by the methods that are well known in the art.
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In one embodiment, the present invention provides methods of treating
disorders
associated with muscarinic receptors, comprising: administering to a patient
in need
thereof an effective amount of a compound of the present invention. Thus, the
present
invention contemplates the various disorders described to be treated herein
and others
which can be treated by such agonists as are appreciated by those skilled in
the art.
A number of the disorders which can be treated by muscarinic agonists are
known
according to established and accepted classifications, while others are not.
For example,
cognition is a complicated and sometimes poorly defined phenomenon. It is,
however,
widely recognized that cognition includes various "domains." These domains
include
short term memory, long term memory, working memory, executive function, and
attention.
It is understood that the compounds of the present invention are useful for
treatment of disorders characterized by a deficit in any of the cognitive
domains listed
above or in other aspects of cognition. Thus the term "cognitive disorders" is
meant to
1 S encompass any disorder characterized by a deficit in one or more cognitive
domain,
including but not limited to short term memory, long term memory, working
memory,
executive function, and attention.
One cognitive disorder to be treated by the present invention is age-related
cognitive decline. This disorder is not well defined in the art, but includes
decline in the
cognitive domains, particularly the memory and attention domains, which
accompany
aging. Another cognitive disorder is mild cognitive impairment. Again, this
disorder is
not well defined in the art, but involves decline in the cognitive domains,
and is believed
to represent a group of patients the majority of which have incipient
Alzheimer's disease.
Another cognitive disorder is cognitive impairment associated with
schizophrenia. The
relationship between cognitive disturbances and other symptoms of
schizophrenia is not
clearly understood at present. It has been observed that some people
experience cognitive
problems much before they develop positive symptoms, while others acquire
cognitive
deterioration after the first episode and with subsequent relapses. Yet
another cognitive
disorder is chemotherapy-induced cognitive impairment. People who undergo
cancer
chemotherapy may experience a decline in cognitive function and this decline
can be long
lasting. Also, a wide variety of insults, including stroke, ischemia, hypoxia,
inflammation, infectious processes and cognitive deficits subsequent to
cardiac bypass
surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head
trauma, perinatal
hypoxia, fetal alcohol syndrome, cardiac arrest, and hypoglycemic neuronal
damage,
vascular dementia, multi-infarct dementia, amylotrophic lateral sclerosis,
chemotherapy,
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and multiple sclerosis can result in cognitive deficits as a sequella which
can be treated
according to the present invention.
Where the disorders which can be treated by muscarinic agonists are known
according to established and accepted classifications, these classifications
can be found in
various sources. For example, at present, the fourth edition of the Diagnostic
and
Statistical Manual of Mental Disorders (DSM-IVT"") (1994, American Psychiatric
Association, Washington, D.C.), provides a diagnostic tool for identifying
many of the
disorders described herein. Also, the International Classification of
Diseases, Tenth
Revision (ICD-10), provides classifications for many of the disorders
described herein.
The skilled artisan will recognize that there are alternative nomenclatures,
nosologies, and
classification systems for disorders described herein, including those as
described in the
DSM-IV and ICD-10, and that terminology and classification systems evolve with
medical scientific progress.
In particularly preferred embodiments, the present invention provides methods
of
treating disorders selected from the group consisting of: cognitive disorders
(including
age-related cognitive disorder, mild cognitive impairment, cognitive
impairment
associated with schizophrenia, and chemotherapy-induced cognitive impairment),
ADHD,
mood disorders (including depression, mania, bipolar disorders), psychosis (in
particular
schizophrenia and schizophreniform disorder), dementia (including Alzheimer's
disease,
AIDS-induced dementia, vascular dementia, and dementia lacking distinctive
histology),
Parkinson's disease, Huntington's Chorea, pain (including acute pain and
chronic pain),
xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body
disease),
aphasia (including primary aphasia and primary aphasia syndromes), aphasia
(including
primary aphasia and primary aphasia syndromes), hypotensive syndromes, and
chronic
colitis (including Crohn's disease), comprising: administering to a patient in
need thereof
an effective amount of a compound of the present invention. That is, the
present
invention provides for the use of a compound of the present invention or
pharmaceutical
composition thereof for the treatment disorders associated with muscarinic
receptors.
It is recognized that the terms "treatment" and "treating" are intended to
include
improvement of the symptomatology associated with each of the disorders
associated
with muscarinic receptors described herein. Also, it is also recognized that
one skilled in
the art may affect the disorders by treating a patient presently afflicted
with the disorders
or by prophylactic ally treating a patient believed to be susceptible to such
disorders with
an effective amount of the compound of the present invention. Thus, the terms
"treatment" and "treating" are intended to refer to all processes wherein
there may be a
slowing, interrupting, arresting, controlling, or stopping of the progression
of the
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disorders described herein, but does not necessarily indicate a total
elimination of all
symptoms, and is intended to include prophylactic treatment of such disorders.
It is understood that the present invention includes adjunctive treatment of
the
disorders described herein. More specifically, the compounds of the present
invention
S are useful to treat disorders in which a cognitive deficit is one of the
symptoms in
combination with a wide variety of other therapeutic agents, in particular, in
combination
with AMPA potentiators; with typical and atypical antipsychotics, including
olanzapine;
with a variety of agents such as mGluR agonists, with NMDA antagonists, with
IL 1-6
inhibitors, with other cholinergics, including cholinesterase inhibitors, such
as tacrine and
donepezil, and compounds that inhibit amyloid protein processing, including
inhibitors of
amyloid precursor protein processing and antibodies directed against amyloid
proteins;
with antidepressants, including SSRIs and SNRIs such as fluoxetine,
paroxetine, and
venlafaxine; and with anxiolytic agents; etc. It is believed that the
combinations above
are synergistically beneficial providing efficacy at doses that are a small
fraction of those
1 S required to produce the same effect with the individual components.
In accordance with the adjunctive treatments described above, the present
invention also provides a product containing a compound of the present
invention and
one or more therapeutic agents selected from the group consisting of AMPA
potentiators;
typical and atypical antipsychotics, including olanzapine; mGluR agonists;
NMDA
antagonists; IL 1-6 inhibitors; cholinesterase inhibitors, such as tacrine and
donepezil;
compounds that inhibit amyloid protein processing, including inhibitors of
amyloid
precursor protein processing and antibodies directed against amyloid proteins;
antidepressants, including SSRIs and SNRIs such as fluoxetine, paroxetine, and
venlafaxine; and anxiolytic agents as a combined preparation for simultaneous,
separate
2S or sequential administration in the treatment of disorders in which a
cognitive deficit is
one of the symptoms. In another embodiment the present invention also provides
for the
use of a compound of the present invention together with one or more
therapeutic agents
selected from AMPA potentiators; typical and atypical antipsychotics,
including
olanzapine; mGluR agonists; NMDA antagonists; IL I-6 inhibitors;
cholinesterase
inhibitors, such as tacrine and donepezil; compounds that inhibit amyloid
protein
processing, including inhibitors of amyloid precursor protein processing and
antibodies
directed against amyloid proteins; antidepressants, including SSRIs and SNRIs
such as
fluoxetine, paroxetine, and venlafaxine; and anxiolytic agents for the
manufacture of a
medicament as a combined preparation for simultaneous, separate or sequential
3S administration in the treatment of disorders in which a cognitive deficit
is one of the
symptoms.
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As used herein, the term "patient" includes a mammal which is afflicted with
one
or more disorders associated with muscarinic receptors. It is understood that
guinea pigs,
dogs, cats, rats, mice, horses, cattle, sheep, pigs, and humans are examples
of animals
within the scope of the meaning of the term.
As used herein, the term "effective amount" of a compound of the present
invention refers to an amount, that is, the dosage which is effective in
treating the
disorders described herein.
An effective amount can be readily determined by the attending diagnostician,
as
one skilled in the art, by the use of conventional techniques and by observing
results
obtained under analogous circumstances. In determining an effective amount,
the dose of
a compound of the present invention , a number of factors are considered by
the attending
diagnostician, including, but not limited to: the compound of the present
invention to be
administered; the co-administration of other therapies, if used; the species
of mammal; its
size, age, and general health; the specific disorder involved; the degree of
involvement or
the severity of the disorder; the response of the individual patient; the mode
of
administration; the bioavailability characteristics of the preparation
administered; the
dose regimen selected; the use of other concomitant medication; and other
relevant
circumstances.
An effective amount of a compound of the present invention is expected to vary
from about 0.01 milligram per kilogram of body weight per day (mg/kg/day) to
about 50
mg/kg/day, and preferable from 0.1 milligram per kilogram of body weight per
day
(mg/kg/day) to about 20 mg/kg/day. More preferred amounts can be determined by
one
skilled in the art.
Of the disorders to be treated according to the present invention a number are
particularly preferred. Particularly preferred disorders include the treatment
of cognitive
disorders (particularly mild cognitive impairment and cognitive impairment
associated
with schizophrenia), Alzheimer's disease, and psychosis, including
schizophrenia.
A number of preclinical laboratory in vitro and in vivo models have been
described for the disorders described herein.
